Histone methylation mechanisms in the comorbidity of anxiety and alcoholism

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Pandey SC, Kyzar EJ, Kokare DM, Teppen TL, Zhang H
Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA

Binge alcohol exposure in adolescence appears to be an important vulnerability factor for the development of alcoholism and psychiatric disorders later in life. Epigenetic modifications in the amygdala are implicated in the persistence of adolescent alcohol exposure-related molecular changes that may be involved in anxiety-like and alcohol drinking behaviors in adulthood. Here, we investigated the effects of adolescent alcohol exposure on the dynamic interactions of histone acetylation and methylation mechanisms and their role in anxiety-like behaviors in adulthood. Adolescent male rats were exposed to 2g/kg ethanol (2 days on/off; AIE) or intermittent n-saline (AIS) during post-natal days (PND) 28-41 prior to behavioral and epigenetic analysis in adulthood. A subset of rats was exposed to an acute ethanol challenge (2 g/kg) in adulthood. AIE exposure produced anxiety-like behaviors and caused decreases in the lysine demethylases Lsd1+8a (a neuron-specific splice variant) and Kdm6b as well as a decrease in the expression of histone acetyltransferases (CBP and p300) in the amygdala compared to AIS-exposed rats in adulthood. It was found that AIE increased repressive H3K9 dimethylation (H3K9me2) in the central (CeA) and medial nucleus of amygdala (MeA) in adulthood without producing any change in permissive H3K4me2 protein levels. Exposure to an acute ethanol challenge (2g/kg) in adulthood attenuated the AIE-induced anxiety-like behaviors. AIE caused an increase in H3K9me2 occupancy at the Bdnf exon IV promoter that also returned to baseline after acute ethanol challenge in adulthood. AIE also produced increases in repressive H3K27me3 levels of the activity-regulated cytoskeletion associated protein (Arc) promoter and gene body, which were normalized by acute ethanol exposure in adulthood. The altered chromatin architecture due to AIE exposure in adulthood is associated with reductions in the expression of synaptic plasticity associated genes including Arc, BDNF and CBP and increased stress-related proteins such as alpha-MSH and melanocortin-4 receptor expression in the amygdala. These results indicate that AIE produces long lasting impacts on histone modifying enzymes involved in histone acetylation and methylation, which may be involved in AIE-induced epigenetic reprogramming and adult psychopathology (Funded by NIAAA-NADIA UO1-AA019971, U24-AA024605 and P50-AA 022538 grants as well as VA senior research career scientist award).